Academic literature on the topic 'Cancer stem cells, pancreatic ductal adenocarcinoma, tumor microenvironment, extracellular matrix'

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.

Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) frequently metastasizes into the peritoneum forming peritoneal carcinomatosis, which are so far not treatable effectively. Metastasis-initiating cells need to acquire beneficial traits including cell plasticity, immune evasion, dormancy state control and organ colonization. These characteristics can be summarized in broad terms into two main processes, epithelial-to-mesenchymal transition (EMT) and stemness. Hyaluronic acid (HA), an extracellular matrix component, is a crucial factor in regulating these processes in PDAC, but it is so far not successfully targetable. Analyzing publicly available databases by gene set enrichment analysis (GSEA), a signature related to HA binding was enriched in tumor samples compared to normal tissue. Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1) was the top contributor to the enrichment score, being the 8th most enriched gene overall. We found that higher HAPLN1 expression correlated with shorter overall survival and that HAPLN1high patients had both, basal subtype and EMT signatures enriched. Moreover, these patients had a signature for peritoneal metastasis significantly enriched, suggesting a higher risk for peritoneal carcinomatosis. To study the role of HAPLN1 on PDAC in vitro, we stably overexpressed HAPLN1 in the murine PDAC cell line KPC. KPC-HAPLN1 cells expressed more EMT markers, more stem-related genes and changed the proteoglycan production from Aggrecan to Versican, which is known to be pro-metastatic. We found that spheroid formation, a feature of stemness, was improved in KPC-HAPLN1 vs KPC. Additionally, embedding these spheroids into matrigel led to an increased invasion of KPC-HAPLN1 cells. KPC-HAPLN1 cells improved KPC cell invasion capacities when co-cultured, indicating a paracrine effect. In vivo, intraperitoneal injection of luciferase expressing KPC cells resulted in higher luciferase activity when tumor cells expressed HAPLN1. Analyzing the peritoneal lavage (PL) from these mice, we obtained significantly more tumor cells in KPC-HAPLN1 injected mice. RNAseq data of tumor cells isolated from tumor nodules and PL showed that KPC-HAPLN1 cells acquired an increased metastatic potential and a strong immunomodulatory phenotype. Thus, we evaluated the immune cell composition of the PL by flow cytometry. Neutrophil and monocyte percentages were drastically reduced in KPC-HAPLN1 bearing mice. On the contrary, these mice had a significant increase in macrophages, which showed a reduction in pro-inflammatory gene expression. We conclude that HAPLN1 expression in tumor cells promotes a hyperplastic phenotype that facilitates invasion and colonization of the peritoneum, among others by creation of a pro-tumoral immune microenvironment. Citation Format: Lena Wiedmann, Francesca De Angelis Rigotti, Nuria Vaquero-Siguero, Elisa Donato, Elisa Espinet, Andreas Trumpp, Andreas Fischer, Juan Rodriguez-Vita. HAPLN1 increases peritoneal carcinomatosis by inducing tumor cell hyperplasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 960.

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant cells within an excessive tumor microenvironment (TME) consisting of extracellular matrix (ECM), fibroblasts, immune cells, and endothelial cells. Research conducted in recent years has particularly focused on cancer-associated fibroblasts (CAFs) which represent the most prominent cellular component of the desmoplastic stroma. Here, we review the complex crosstalk between CAFs, tumor cells, and other components of the TME, and illustrate how these interactions drive disease progression. We also discuss the emerging field of CAF heterogeneity, their tumor-supportive versus tumor-suppressive capacity, and the consequences for designing stroma-targeted therapies in the future.

Abstract Introduction The immunosuppressive tumor microenvironment promotes progression of pancreatic ductal adenocarcinoma (PDAC). γδ T cells infiltrate the pancreatic tumor stroma and support tumorigenesis through αβ T cell inhibition. Pancreatic stellate cell (PSC) activation contributes to pancreatic fibrosis in PDAC, limiting the delivery and efficacy of therapeutic agents. Whether γδ T cells have direct effects on PSC activation is unknown. Methods In this study, we analyzed tumor tissue from 68 patients with PDAC and determined the frequency and location of γδ T cells using immunohistochemistry and immunofluorescence. PDAC samples from the TCGA database with low and high TRGC2 expression were correlated with the expression of extracellular matrix genes. Further, PSCs were isolated from pancreatic tumor tissue and co-cultured with γδ T cells for 48 hours and cytokine production was measured using a cytometric bead array. Results γδ T cells infiltrated the pancreatic tumor stroma and were located in proximity to PSCs. A high infiltration of γδ T cells was associated with increased expression of several extracellular matrix genes in human PDAC. In vitro, γδ T cells stimulated IL-6 production by PDAC-derived PSCs. Conclusion γδ T cells activated PSCs and modulation of this interaction may enhance the efficacy of combinational therapies in human PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier to hinder chemotherapy and actively contributes to tumor progression and metastasis. CAFs represent a multifunctional subset of PDAC microenvironment and contribute to tumor initiation and progression through ECM deposition and remodeling, as well as the secretion of paracrine factors. Attempts to resolve desmoplasia by targeting CAFs can render an adverse outcome, which is likely due to CAFs heterogeneity. Recent reports describe subsets of CAFs that assume more secretory functions, in addition to the typical myofibroblast phenotype. Here, we review the literature and describe the relationship between CAFs and inflammation and the role of the secretory-CAFs in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with only a few effective therapeutic options. A characteristic feature of PDAC is its unique tumor microenvironment (TME), termed desmoplasia, which shows extensive fibrosis and extracellular matrix deposition, generating highly hypoxic and nutrient-deprived conditions within the tumor. To thrive in this harsh TME, PDAC undergoes extensive metabolic rewiring that includes the altered use of glucose and glutamine, constitutive activation of autophagy-lysosomal pathways, and nutrient acquisition from host cells in the TME. Notably, these properties support PDAC metabolism and mediate therapeutic resistance, including immune suppression. A deeper understanding of the unique metabolic properties of PDAC and its TME may aid in the development of novel therapeutic strategies against this deadly disease.

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment.

E’ stato dimostrato che le cellule staminali tumorali (cancer stem cells, CSC) sono responsabili dello sviluppo neoplastico, della formazione delle metastasi, della resistenza al trattamento con chemioterapici e dello sviluppo di recidive. Inoltre, il microambiente tumorale dell’adenocarcinoma pancreatico duttale (pancreatic ductal adenocarcinoma, PDAC) è ricco di matrice extracellulare, la quale promuove la crescita tumorale e la resistenza alle terapie. Lo scopo di questa tesi è stato l’ottenimento e la successiva caratterizzazione di CSC da linee cellulari di PDAC. Le CSC di PDAC si sono rivelate generalmente più resistenti all’azione di cinque farmaci chemioterapici rispetto alle cellule parentali e hanno mostrato un’aumentata espressione dei marcatori staminali EpCAM e CD44v6 e una diminuita espressione del marcatore epiteliale E-caderina. Inoltre, esse hanno mostrato maggiori capacità tumorigeniche e metastatiche rispetto alle cellule parentali quando inoculate in topi nudi atimici. Quando coltivate su diverse matrici in modelli tridimensionali (3D), le CSC di PDAC e le cellule parentali hanno acquisito una diversa morfologia. In particolare, solo le CSC hanno sviluppato strutture tubulari in presenza di Matrigel e hanno mostrato un aumento dell’espressione dei marcatori endoteliali CD34, CD31 e CD144 e dei fattori pro-angiogenici IGFBP1 ed eNOS. Inoltre, le CSC hanno mostrato un profilo angiogenico superiore rispetto alle cellule parentali, come dimostrato dalla secrezione di diversi fattori pro-angiogenici. Quando inoculate in topi nudi, le CSC hanno sviluppato tumori con una rete vascolare più intensa e con vasi di calibro maggiore rispetto ai tumori generati dalle cellule parentali. Infine, quando direttamente coltivate con cellule staminali mesenchimali del midollo osseo (bone marrow-mesenchymal stem cells, BM-MSC) del microambiente tumorale, le cellule di PDAC hanno mostrato una diminuita espressione dei marcatori staminali EpCAM e CD24. Nel complesso questi risultati dimostrano che da linee cellulari di PDAC è possibile derivare CSC con caratteristiche tumorali clinicamente rilevanti che costituiscono un modello necessario per lo studio della biologia del PDAC. I modelli 3D sono di cruciale importanza per lo studio sia del ruolo del microambiente nella biologia del tumore sia della capacità delle CSC di PDAC di formare nuovi vasi nelle fasi iniziali dello sviluppo tumorale. Infine, le BM-MSC possono avere un ruolo nella regolazione del differenziamento cellulare nel PDAC.
It has been reported that cancer stem cells (CSCs) are responsible for tumor initiation, metastasis, chemoresistance, and relapse. Furthermore, the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is rich of extracellular matrix (ECM), which supports tumor growth and chemotherapy resistance. The aim of this thesis was to obtain and characterize CSCs derived from PDAC established cell lines. PDAC CSCs were generally more resistant to the action of five anti-cancer drugs than parental cell lines and were characterized by an increased expression of the stem cell markers EpCAM and CD44v6, and a decreased expression of the epithelial state marker E-cadherin. Furthermore, PDAC CSCs were more tumorigenic and possessed a higher metastatic activity than parental cells when injected into nude mice. When cultured on the top of several matrices, CSCs and the parental cells acquired a different morphology. In particular, only CSCs developed tube-like structures in the presence of Matrigel, and showed an increased expression of the endothelial cell markers CD34, CD31, and CD144, and of the pro-angiogenic factors IGFBP1 and eNOS. Furthermore, PDAC CSCs demonstrated a higher angiogenic profile with respect to the parental cells, as demonstrated by the secretion of several pro-angiogenic factors. When injected into nude mice, PDAC CSCs gave rise to tumors with a more intense vascular network with vessels with larger caliper than the tumors generated by parental cells. Additionally, when directly co-cultured with microenvironment bone marrow-mesenchymal stem cells (BM-MSCs), PDAC cells showed a decreased expression of the stem cell markers EpCAM and CD24. Taken together these results demonstrate that CSCs derived from PDAC cell lines possess all the characteristics of the clinically relevant tumor, rendering them a model to deeply understand PDAC biology. Three-dimensional cell culture models are of crucial relevance to study the role of the microenvironment on tumor biology and of the capability of PDAC CSCs for the sprouting of new vessels at the initial phases of tumor development. Finally, BM-MSCs may play a role in the regulation of PDAC cellular differentiation.